Two novel and one recurrent missense mutation in the factor XIII A gene intwo Dutch patients with factor XIII deficiency

Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive dis order, usually attributed to a defect in the FXIII A subunit, whose genetic basis has been studied in a number of cases. We describe here the genetic variations found in two unrelated patients with FXIII deficiency. Both pati ents, under prophylactic substitution with FXIII concentrate, showed low pl asma FXIII A subunit antigen levels with undetectable A subunit antigen in the platelets and normal plasma B antigen levels, which indicate that the d efects are present in the A subunit of the molecule. Both probands were het erozygous for a previously reported G -->A transversion in exon 8 of the FX III A subunit gene (Arg326Gln substitution). Proband 1 was also heterozygou s for a novel G -->T transversion in exon 7, which predicts a Val316Phe sub stitution. Two of her sons were heterozygous for this mutation and showed l ow FXIII activity and FXIII A subunit antigen levels. Val316 is a well-cons erved amino acid among the transglutaminase family, located within the core domain, close to the Cys314 member of the catalytic triad. Proband 2 had a unique 2-bp (TT) insertion in one of the alleles within or adjacent to the -7 to -20 T tail of intron A. This insertion was not found in 50 healthy i ndividuals, which supports this being the second mutation in this patient.